Prostate cancer (PCa) is a common malignancy in the male reproductive system. In 2008, there were 903,500 new cases of prostate cancer and 258,400 deaths due to prostate cancer globally. Among them, new cases of prostate cancer account for 14% of all new cases of male tumors, ranking 2nd in new cases of male tumors; deaths due to prostate cancer account for 6% deaths of male cancers, ranking 6th in deaths of male cancers. Deaths due to prostate cancer account for 9% deaths of male cancers, ranking 2nd in deaths of male cancers following lung cancer. Due to the deterioration of environmental pollution in recent years, accelerated aging of the population, and changes in people's dietary patterns, the incidence and mortality of prostate cancer have increased rapidly. Now the prostate cancer has become one of the important diseases affecting the male health in China.
The effect of androgen on the growth of prostate cancer cells is mediated by androgen receptor (AR) signaling pathway. Clinically, the level of prostate-specific antigen (PSA) in patients is observed by changes in AR signal, thereby patients with prostate cancer are diagnosed and treated. Traditional castration therapy does not completely inhibit the production of androgens or the expression of the target gene of androgen receptor. When the androgen synthase is overexpressed, the level of androgens in the tumor will increase.
Cytochrome oxidase P450 c17 (CYP17) is expressed in the testis, adrenal gland and normal prostate tissues, and it is also expressed in prostate cancer cells. 17α-hydroxylase and C17,20-lyase in CYP17 are key enzymes in androgen biosynthesis, which can promote the conversion of steroid progesterone and pregnenolone into C19 androstenedione and dehydroepiandrosterone, respectively, and both in turn are converted into testosterone and dihydrotestosterone (DHT).
Based on the above studies, the prevention and treatment of prostate cancer is an urgent task. Researching and developing inhibitors of CYP17 enzyme is an important direction for drug treatment of prostate cancer. As a novel inhibitor of CYP17 enzyme, abiraterone acetate was developed by Centocor Ortho to treat prostate cancer. Abiraterone acetate was approved by the FDA on Apr. 28, 2011, and was used in combination with prednisone to treat castration-resistant prostate cancer under the trade name Zytiga. On Jul. 28, 2011, Zytiga was approved by the Health Ministry of Canada. For patients with prostate cancer, hormone testosterone stimulates the growth of the tumor. Castration therapy, including medication or surgery, can reduce testosterone production or block testosterone, but this treatment does not inhibit the production of androgens in other parts of the body. Prostate cancer can still continue to grow. Abiraterone targetedly inhibits the activity of the CYP17 enzyme that regulates androgen production, reducing the production of androgens and slowing tumor growth. Median survival for patients treated with abiraterone acetate plus prednisone is 3.9 months longer than that of patients treated with placebo plus prednisone (14.8 and 10.9 months, respectively, p<0.0001), i.e., the risk of death is reduced by 35%. The common adverse effects are mineralocorticoid-related risk events, including urinary retention, hypokalemia, and hypertension.
However, abiraterone resistance has emerged during the treatment of prostate cancer. Therefore, there is still a need to develop more active and potent drugs for prostate cancer.